Cancer, or malign neoplasm, is a disease characterized by a population of cells that grows and divides indefinitely, invading and destroying various tissues in a process known as metastasis. Cancer is usually classified according to the tissue from which the cancerous cells originate, as well as the normal cell type they most resemble.
Nearly all cancers are caused by genetic abnormalities. These anomalies can be caused by carcinogenic agents (e.g. smoking, radiation, chemicals or infectious agents) or can be inherited, and thus are present in all cells from birth. Genetic abnormalities found in cancer typically affect two general classes of genes. The genes that promote cancer, oncogenes, are typically activated in cancer cells, providing those cells with new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries and the ability to become stable in several tissues. In addition, tumor suppressor genes are often inactivated in cancer cells, resulting in loss of normal functions of these cells as an accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.
Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy.
Most drugs used in cancer chemotherapy somehow interfere with the cell cycle and therefore are usually classified according to the effect thereof on the cell cycle: a) nonspecific chemo cycle—act on cells that are proliferating or not in the cycle, as for example, nitrogen mustard b) cycle-specific—act only on cells that are proliferating, such as cyclophosphamide and c) phase-specific—they act in certain phases of cell cycle, such as, methotrexate (S phase), placitaxel (M phase), etoposide (G2) and vincristine (M phase).
Chemotherapy can be done by applying one or more chemotherapeutic agents. The use of a single drug (monochemotherapy) is ineffective in inducing significant partial or complete responses in most tumors and currently has a very restricted use. Chemotherapy is of proven effectiveness and aims to achieve cell populations in different phases of the cell cycle, using the synergistic action of drugs, reduce the development of drug resistance and to promote greater response per dose.
The drugs used in cancer chemotherapy affect both the normal and the neoplasic cells. For this reason, the vast majority of treatments with conventional chemotherapy in either mono- or multidrug therapy is associated with a variety of undesirable side effects of these compounds, such as anemia, severe immunosuppression, alopecia, hepatotoxicity, mild gastrointestinal damage and peripheral neuropathy.
Most substances used in cancer treatment can damage DNA, causing the death of tumor cells. In addition to reaching the target cells, these substances can also be absorbed by normal cells and may cause the occurrence of mutations and genotoxic effects, leading to the appearance of secondary tumors. Thus, in assessing the clastogenic potential of chemicals used in chemotherapy, one seeks to implement treatment protocols and/or other drugs that can minimize the effects of the used agents.
Anticancer drugs such as cyclophosphamide, etoposide and paclitaxel, are used in antitumor therapy, but have great potential to cause mutagenicity in bone marrow cells, and DNA damage in patients taking said medicine alone or in combination (Mazu et al. Mutat. Res, 309 (2): pp. 219-213, 1994, Shuko, Y. Human and exp. Toxicol., 23 (5):245-250, 2004, Branham, M T Mutat. Res., 560 (1): 11-17, 2004, Huang, R. CA Cancer J. Clin., 59:42-55, 2009). Thus, the decline of the mutagenic action of antitumor compounds such as paclitaxel, cyclophosphamide and etoposide is related to the association of some drugs such as dexrazoxane, amifostine and mesna.
However, these co-adjuvant drugs have important disadvantages. Dexrazoxane reduces the toxicity of etoposide, but has significant side effects as well as rates of cell damage in an excess of 45% [Attia et al. Cancer Chem. Pharmacol., 2009 (Epub ahead of print)]. Amifostine has reduced toxicity when used in combination with cisplatin or paclitaxel (Marcu L G. Eur J Cancer Care (Engl), 18 (2): 116-123, 2009), but it has from 50 to 60% of cell damages. Mesna in combination with paclitaxel has moderate antimutagenic action and the presence of undesirable side effects (Souza et al., Rev. Bras. Hemat. Hemoter., 22 (2): 123-128, 2000, Chen et al. Gen. Cancer There., 14 (12): 935-944, 2007; Vilar et al. Braz. J. Biol., 68 (1): 141-147, 2008).
In light of the above, it is desirable to develop adjuvant components to reduce the side effects of cancer chemotherapeutic agents and to increase their toxicity to tumor cells.
Metal salts of the compound 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one, such as sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienil]-2-methoxyphenolate (metal phenolate) were obtained by J. Quincoces and colleagues (patent documents PCT/BR2007/000175 and PI0602640-0), and showed significant antiproliferative activity in tumor cell lines. In addition, these compounds were also able to inhibit the formation of metastases (Faião-Flores et al., Applied Cancer Res, 28 (2): 72-79, 2008). However, until now there have not been described in the literature that these compounds do potentiate the adjuvant, antimetastatic, cytoprotective and antimutagenic actions when associated with other antitumor drugs.